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Background: The association between skeletal muscle and adipose tissue (body composition) and early response using positron emission tomography (PET) in pediatric Hodgkin lymphoma (HL) remains unstudied., Methods: Patients enrolled on Children's Oncology Group studies AHOD0031 (intermediate-risk HL) and AHOD0831 (high-risk HL) with digital abdominal computed tomography (CT) scans at diagnosis and PET scans after 2 cycles (PET2) were included. Two consecutive slices at the third lumbar vertebra were identified and skeletal muscle index (SMI, in cm2/m2) and total adipose tissue index (TATI, in cm2/m2) were calculated using sliceOmatic (Magog, Canada) and height at diagnosis. SMI and TATI were divided into quintiles (Q1 [lowest] to Q5 [highest]). Body mass index (BMI) was calculated using height and weight at diagnosis. The association between baseline body composition (SMI, TATI, BMI) and positive PET2 was examined using logistic regression, adjusting for age at diagnosis, sex, race/ethnicity, stage, histology, bulk disease and 'B' symptoms., Results: Among 1,033 included patients, PET2 was positive in 314 (30.4%). SMI was not associated with positive PET2. Extremes of TATI were associated with positive PET2, when compared with the middle TATI quintile (reference: Q3; odds ratio [ORQ1]=1.63, 95% confidence interval [CI]=1.03-2.60, P=0.04; ORQ2=1.82, 95%CI=1.17-2.82, P=0.008; ORQ5=1.94, 95%CI=1.23-3.05, P=0.005). The association between BMI in obesity range and positive PET2 trended towards significance (OR=1.42, 95%CI=0.98-2.04, P=0.06; ref=normal weight)., Conclusions: Extremes of adipose tissue at diagnosis influences early response among pediatric HL., Impact: Validation of results from this study could inform studies investigating body composition-based chemotherapy dosing.

Importance: Retrieval strategies for children, adolescents, and young adults with relapsed classic Hodgkin lymphoma (cHL) aim to maintain efficacy while minimizing long-term toxic effects. Children, adolescents, and young adults with low-risk, relapsed cHL may benefit from replacing high-dose chemotherapy and autologous stem cell transplant with less intensive involved-site radiotherapy (ISRT)., Objective: To evaluate a risk-stratified, response-adapted, transplant-free approach for treatment of children, adolescents, and young adults with low-risk relapsed cHL with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response and ISRT (30.0 to 30.6 Gy)., Design, Setting, and Participants: CheckMate 744 (R1 cohort) was a phase 2, nonrandomized, single-arm study enrolling children, adolescents, and young adults aged 5 to 30 years with low-risk cHL between September 25, 2017, and December 16, 2020, across the US, Canada, and Europe. Data were analyzed from September 2017 to November 2022., Exposures: Patients received 4 cycles of nivolumab plus BV induction; patients with complete metabolic response (CMR) received an additional 2 cycles of nivolumab plus BV while patients with suboptimal response received 2 cycles of BV plus bendamustine intensification. Patients with CMR after induction or intensification received ISRT consolidation., Main Outcomes and Measures: Prespecified coprimary end points were CMR rate (Lugano 2014 classification) any time before ISRT and 3-year event-free survival (EFS) rate, per blinded independent central review (BICR)., Results: Of 28 included patients treated in the low-risk cohort, 18 (64%) were female, and the median (range) age was 17 (6-27) years. At a median (range) follow-up of 31.9 (2.2-55.3) months, CMR per BICR any time before ISRT was 93% (26 of 28; 90% CI, 79.2-98.7; objective response rate [ORR], 100%), and 23 of 28 (82%) achieved CMR per BICR after 4 cycles of nivolumab plus BV (ORR, 96.4%). Kaplan-Meier estimates of EFS and progression-free survival rates at 3 years were 87% (3 of 18; 90% CI, 69.5-94.7) and 95% (1 of 18; 90% CI, 76.7-99.0), respectively. During induction, 22 patients (79%) had treatment-related adverse events, including 7 with grade 3 or 4 adverse events, 2 with anemia, 1 with neutropenia, and 6 with immune-mediated adverse events. Serious adverse events leading to discontinuation occurred in 2 patients., Conclusions and Relevance: This nonrandomized clinical trial found that for children, adolescents, and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with nivolumab plus BV and ISRT offered high CMR rates and high 3-year EFS rate, with a safety profile consistent with that of each agent used., Trial Registration: ClinicalTrials.gov Identifier: NCT02927769.

Staging of pediatric Hodgkin lymphoma is currently based on the Ann Arbor classification, incorporating the Cotswold modifications and the Lugano classification. The Cotswold modifications provide guidelines for the use of CT and MRI. The Lugano classification emphasizes the importance of CT and PET/CT in evaluating both Hodgkin lymphoma and non-Hodgkin lymphoma but focuses on adult patients. This article presents consensus guidelines that extend the traditional classifications used for adult Hodgkin lymphoma staging and provide rigorous definitions of lymph node groups based on MRI, CT, and fluorodeoxyglucose PET/CT findings. This allows consistent terminology and definitions, using metabolic and morphologic imaging to identify affected lymph nodes or extranodal regions and organs. The pattern of involvement, together with other individual risk factors, determines treatment strategy. In case of inadequate response to chemotherapy, radiation therapy is often required. Standardization of staging definitions for pediatric Hodgkin lymphoma is necessary for comparing treatment outcomes between North American and European clinical trials and a prerequisite for clear communication during tumor boards and central review. This comprehensive imaging atlas is intended to provide regional criteria for nodal involvement and to serve as a standardized guide for the anatomic assignment of lymph node involvement in pediatric Hodgkin lymphoma., (© RSNA, 2025 See also the editorial by Humphries in this issue.)

Importance: Pediatric patients with cancer commonly experience severely bothersome symptoms. The effectiveness of routine symptom screening with symptom feedback and symptom management care pathways is unknown., Objective: To determine whether thrice-weekly symptom screening with symptom feedback and management care pathways, compared with usual care, improves overall self-reported symptom scores measured by the Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer., Design, Setting, and Participants: This cluster randomized trial enrolled participants between July 2021 and August 2023 from 20 pediatric cancer centers in the US. Patients newly diagnosed with cancer aged 8 to 18 years receiving any cancer treatment were included. Twenty sites were randomized to provide symptom screening (n = 10) vs usual care (n = 10); 221 participants were enrolled at intervention sites and 224 participants at control sites. The date of final follow-up was October 18, 2023., Intervention: Symptom screening included providing thrice-weekly symptom screening prompts to participants, email alerts to the health care team, and locally adapted symptom management care pathway implementation., Main Outcomes and Measures: The primary outcome was self-reported total SSPedi score at week 8 (range, 0-60; higher scores indicate more bothersome). Secondary outcomes were Patient-Reported Outcomes Measurement Information System Fatigue score (mean [SD] score, 50 [10]; higher scores indicate more fatigue), Pediatric Quality of Life 3.0 Acute Cancer Module scores (range, 0-100; higher scores indicate better health), symptom documentation and interventions at week 8, and unplanned health care encounters., Results: A total of 445 participants (median [range] age, 14.8 [8.1-18.9] years; 58.9% males) were enrolled. The mean (SD) 8-week SSPedi score was 7.9 (7.2) in the symptom screening group vs 11.4 (8.7) in the usual care group. Symptom screening was associated with significantly better 8-week total SSPedi scores (adjusted mean difference, -3.8 [95% CI, -6.4 to -1.2]) and less bothersome individual symptoms, with 12 of 15 symptoms being statistically significantly reduced. There was no difference in fatigue or quality of life. The mean (SD) number of emergency department visits was 0.77 (1.12) in the symptom screening group and 0.45 (0.81) in the usual care group. There were significantly more emergency department visits in the symptom screening group (rate ratio, 1.72 [95% CI, 1.03-2.87])., Conclusions: Symptom screening with symptom feedback and symptom management care pathways was associated with improved symptom scores and increased symptom-specific interventions. Future work should integrate symptom screening into routine clinical care., Trial Registration: ClinicalTrials.gov Identifier: NCT04614662.

Purpose: Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)-based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines., Methods: We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination., Results: Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures., Conclusion: This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Treatment of acute lymphoblastic leukemia (ALL) is associated with neurocognitive deficits in young children. While computerized measures have been utilized in pediatric oncology research, they exclude patients below the age of 4 years. Patients enrolled on "Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents" were offered participation in an optional neurocognitive study. Three-year old patients did not differ from 4-year-old patients in their ability to perform or complete the tests. Including patients diagnosed at age 3 will serve to improve our understanding of at-risk patients and their neurocognitive trajectory both during and after treatment., (© 2024 Wiley Periodicals LLC.)

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10 -8 ). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10 -6 ). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10 -3 ). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Poverty-exposed children with cancer are more likely to experience adverse outcomes. Supplemental Nutrition Assistance Program (SNAP) benefits improve food insecurity and child health outcomes, and could be used to mitigate disparities. We conducted a secondary analysis of parent-reported data collected in a frontline pediatric leukemia trial (NCT03020030) to assess SNAP eligibility (proxied by other means-tested program participation) and participation. At diagnosis, 105/287 families (37%) were SNAP-eligible, of whom 53 (50%) were SNAP participants. At 6 months, 104/257 families (41%) were SNAP-eligible, and 59 (57%) were SNAP participants. Interventions to increase benefits participation during childhood cancer treatment represent an immediate opportunity to reduce disparities., (© 2024 Wiley Periodicals LLC.)

Classic Hodgkin lymphoma (HL) is rare disease, with an incidence of approximately 85,000 patients globally per year and a predilection for adolescents and young adults (ages 15-39). Since the introduction of combination chemotherapy in the 1960's and radiation dating back to the early 1900's, therapeutic options and by extension, clinical outcomes have improved dramatically with 5-year overall survival (OS) approaching 90% today. [1](#ref-0001) Advances in understanding HL biology have additionally facilitated development of targeted agents and immunotherapy which have further improved short and long-term outcomes. Despite continued improvements in up-front and salvage therapy, long-term survivors of HL experience several treatment-associated late toxicities, thus, along with efforts to improve therapeutic efficacy, efforts to reduce late effects remain a high-priority in the field., (© 2023 John Wiley & Sons Ltd.)

Background: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients., Methods: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause., Results: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation., Conclusions: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.)., (Copyright © 2024 Massachusetts Medical Society.)

PURPOSEThere have been no previous longitudinal assessments of health-related quality of life (HRQoL) during treatment for pediatric Hodgkin lymphoma (HL). The addition of brentuximab vedotin (BV) to a multidrug chemotherapy backbone demonstrated superior efficacy to standard chemotherapy for patients with pediatric high-risk HL in the AHOD 1331 trial. However, the impact on HRQoL is unknown.PATIENTS AND METHODSAfter treatment random assignment, 268 participants older than 11 years were enrolled in a prespecified, longitudinal, patient-reported outcomes substudy. HRQoL was assessed using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale before treatment (T1) and at cycle 2 (T2), cycle 5 (T3), and end of treatment (T4). A clinically meaningful increase in HRQoL was considered 7 points on the CHRIs-Global. Multivariable linear regression estimated associations between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated changes in HRQoL across the treatment arm.RESULTSParticipant characteristics were balanced by treatment arm. Ninety-three percent of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 77% at T4. At T1, female sex and fever ( P < .05) were each associated with worse HRQoL. By T2, participants in the BV arm experienced a statistically and clinically significant improvement in HRQoL (β = 7.3 [95% CI, 3.2 to 11.4]; P ≤ .001), which was greater than the change in the standard arm (difference in change β = 5.1 [95% CI, -0.2 to 10.3]; P = .057). The standard arm did not experience a statistically or clinically significant increase in HRQoL until T4 (β = 9.3 [95% CI, 4.7 to 11.5]; P < .001).CONCLUSIONThese data demonstrate successful collection of serial HRQoL from youth with high-risk pediatric HL and improvement in HRQoL over the course of initial therapy, sooner and to a greater extent in the group receiving the novel agent BV.

Purpose: Automatic quantification of longitudinal changes in PET scans for lymphoma patients has proven challenging, as residual disease in interim-therapy scans is often subtle and difficult to detect. Our goal was to develop a longitudinally-aware segmentation network (LAS-Net) that can quantify serial PET/CT images for pediatric Hodgkin lymphoma patients., Materials and Methods: This retrospective study included baseline (PET1) and interim (PET2) PET/CT images from 297 patients enrolled in two Children's Oncology Group clinical trials (AHOD1331 and AHOD0831). LAS-Net incorporates longitudinal cross-attention, allowing relevant features from PET1 to inform the analysis of PET2. Model performance was evaluated using Dice coefficients for PET1 and detection F1 scores for PET2. Additionally, we extracted and compared quantitative PET metrics, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in PET1, as well as qPET and ΔSUVmax in PET2, against physician measurements. We quantified their agreement using Spearman's ρ correlations and employed bootstrap resampling for statistical analysis., Results: LAS-Net detected residual lymphoma in PET2 with an F1 score of 0.606 (precision/recall: 0.615/0.600), outperforming all comparator methods (P<0.01). For baseline segmentation, LAS-Net achieved a mean Dice score of 0.772. In PET quantification, LAS-Net's measurements of qPET, ΔSUVmax, MTV and TLG were strongly correlated with physician measurements, with Spearman's ρ of 0.78, 0.80, 0.93 and 0.96, respectively. The quantification performance remained high, with a slight decrease, in an external testing cohort., Conclusion: LAS-Net demonstrated significant improvements in quantifying PET metrics across serial scans, highlighting the value of longitudinal awareness in evaluating multi-time-point imaging datasets.

Abstract: Hodgkin lymphoma (HL) involving the central nervous system (CNS) is exceedingly rare. Information regarding the presentation, management, treatment, and outcome of patients with CNS HL is limited to case reports or small series. We describe 45 pediatric patients with 55 extra-axial CNS lesions at diagnosis with HL from a cohort of 4995 patients enrolled on Children's Oncology Group AHOD1331 and the European Network for Pediatric Hodgkin lymphoma C1 and C2 trials, with an overall incidence of 0.9%. Up to 82.2% of patients had a single CNS lesion in the thoracic, lumbar, or sacral spine. In the evaluated cohort, HL did not occur within the CNS parenchyma. Lesions extended into the extra-axial CNS space from adjacent soft tissue or bone and never directly infiltrated through the dura into the brain or spinal cord. Patients with CNS involvement had a twofold greater incidence of extranodal lesions than previously reported cohorts without CNS involvement. After 2 cycles of chemotherapy, 89.1% of CNS lesions demonstrated a complete metabolic response and >75% decrease in volume. Thirteen CNS lesions (23.6%) received irradiation; none were sites of disease relapse. Relapse occurred at the site of 2 lesions involving the CNS, both of which had an adequate interim response to chemotherapy. In summary, we present, to our knowledge, the largest reported cohort of systemic HL involving the CNS at diagnosis, demonstrating that these lesions originate from surrounding tissues, extend into the extra-axial CNS space, and respond similarly to other nodal and extranodal disease. The trials were registered at www.clinicaltrials.gov as #NCT02166463, #NCT00433459, and #NCT02684708., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for classic Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children's Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) with bleomycin containing doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC; standard arm) in patients with high-risk cHL ages 2-21 years., Methods: AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by the presence of dose modification., Results: Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 v 19.8%, P = .91). CIPN dose modifications occurred more frequently in the BV arm (9.5% v 2.8%, P = .001); however, most patients with CIPN on the BV arm received full-dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, although older age was significantly associated with the risk of VCR dose modifications for CIPN., Conclusion: A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331 minimized the effect of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV arm.

Purpose: The purpose of the study was to evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma in the phase III AHOD1331 study., Experimental Design: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation., Results: There were no visible trends in disease characteristics across pediatric age subgroups, whereas BW increased with age. Observed antibody-drug conjugate exposures in patients ages <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks, as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival was seen in younger subgroups: 3-year event-free survival rates were 96.2% (2-<12 years) and 92.0% (12-<18 years), with no events observed in those ages <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children., Conclusions: No further adjustments based on age or BW are required for the BV dosage (1.8 mg/kg every 3 weeks) approved in children., (©2024 The Authors; Published by the American Association for Cancer Research.)

Data commons have proven to be an indispensable avenue for advancing pediatric cancer research by serving as unified information technology platforms that, when coupled with data standards, facilitate data sharing. The Pediatric Cancer Data Commons, the flagship project of Data for the Common Good (D4CG), collaborates with disease-based consortia to facilitate development of clinical data standards, harmonization and pooling of clinical data from disparate sources, establishment of governance structure, and sharing of clinical data. In the interest of international collaboration, researchers developed the Hodgkin Lymphoma Data Collaboration and forged a relationship with the Pediatric Cancer Data Commons to establish a data commons for pediatric Hodgkin lymphoma. Herein, we describe the progress made in the formation of Hodgkin Lymphoma Data Collaboration and foundational goals to advance pediatric Hodgkin lymphoma research., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Large language models (LLMs) have shown promise in accelerating radiology reporting by summarizing clinical findings into impressions. However, automatic impression generation for whole-body PET reports presents unique challenges and has received little attention. Our study aimed to evaluate whether LLMs can create clinically useful impressions for PET reporting. To this end, we fine-tuned twelve open-source language models on a corpus of 37,370 retrospective PET reports collected from our institution. All models were trained using the teacher-forcing algorithm, with the report findings and patient information as input and the original clinical impressions as reference. An extra input token encoded the reading physician's identity, allowing models to learn physician-specific reporting styles. To compare the performances of different models, we computed various automatic evaluation metrics and benchmarked them against physician preferences, ultimately selecting PEGASUS as the top LLM. To evaluate its clinical utility, three nuclear medicine physicians assessed the PEGASUS-generated impressions and original clinical impressions across 6 quality dimensions (3-point scales) and an overall utility score (5-point scale). Each physician reviewed 12 of their own reports and 12 reports from other physicians. When physicians assessed LLM impressions generated in their own style, 89% were considered clinically acceptable, with a mean utility score of 4.08/5. On average, physicians rated these personalized impressions as comparable in overall utility to the impressions dictated by other physicians (4.03, P = 0.41). In summary, our study demonstrated that personalized impressions generated by PEGASUS were clinically useful in most cases, highlighting its potential to expedite PET reporting by automatically drafting impressions., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Hodgkin lymphoma (HL) represents one of the more common cancers occurring in adolescent and young adults (AYAs) age 15-39 years. Despite a generally high cure rate, age-related differences in HL biology and the optimal therapeutic approaches including supportive care and risks for long-term adverse effects in the AYA population remain understudied. After an overview of HL epidemiology and biology in the AYA population, this review will cover frontline pediatric and adult treatment approaches. Recently completed and ongoing studies will foster harmonization of risk group definition and trial eligibility criteria across the AYA spectrum, enabling more rapid progress. In addition to treatment approaches, an evolving holistic care approach to AYA HL will result in enhanced understanding of unique challenges, and continued improved short- and long-term outcome for these patients.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain., Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials., Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023., Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane., Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease., Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines., Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN., Methods: Youth (11+ years) and parents of all children (5-17.9 years) with newly diagnosed high-risk HL enrolled on Children's Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach's alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model., Results: 306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach's alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41-0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (β = - 2.83, p < 0.001) and parent-proxy raters (β = - 1.99, p < 0.001)., Conclusions: High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial., Clinical Trial Information: Clinical Trials Registry, NCT02166463. Registered 18 June 2014, https://clinicaltrials.gov/ct2/show/study/NCT02166463., (© 2023. The Author(s).)

Background: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL., Procedure: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue., Results: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy., Conclusions: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase., (© 2023 Wiley Periodicals LLC.)

The International Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) seeks to provide an appropriate, universal differentiation between E-lesions and stage IV extranodal disease in Hodgkin lymphoma (HL). A literature search was performed through the PubMed and Google Scholar databases using the terms "Hodgkin disease," and "extranodal," "extralymphatic," "E lesions," "E stage," or "E disease." Publications were reviewed for the number of participants; median age and age range; diagnostic modalities used for staging; and the definition, incidence, and prognostic significance of E-lesions. Thirty-six articles describing 12 640 patients met the inclusion criteria. Most articles reported staging per the Ann Arbor (72%, 26/36) or Cotswolds modification of the Ann Arbor staging criteria (25%, 9/36), and articles rarely defined E-lesions or disambiguated "extranodal disease." The overall incidence of E-lesions for patients with stage I-III HL was 11.5% (1330/11 602 unique patients). Available stage-specific incidence analysis of 3888 patients showed a similar incidence of E-lesions in stage II (21.2%) and stage III (21.9%), with E-lesions rarely seen with stage I disease (1.1%). E-lesions likely remain predictive, but we cannot unequivocally conclude that identifying E-lesions in HL imparts prognostic value in the modern era of the more selective use of targeted radiation therapy. A harmonized E-lesion definition was reached based on the available evidence and the consensus of the SEARCH working group. We recommend that this definition of E-lesion be applied in future clinical trials with explicit reporting to confirm the prognostic value of E-lesions., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: To determine if fine-tuned large language models (LLMs) can generate accurate, personalized impressions for whole-body PET reports., Materials and Methods: Twelve language models were trained on a corpus of PET reports using the teacher-forcing algorithm, with the report findings as input and the clinical impressions as reference. An extra input token encodes the reading physician's identity, allowing models to learn physician-specific reporting styles. Our corpus comprised 37,370 retrospective PET reports collected from our institution between 2010 and 2022. To identify the best LLM, 30 evaluation metrics were benchmarked against quality scores from two nuclear medicine (NM) physicians, with the most aligned metrics selecting the model for expert evaluation. In a subset of data, model-generated impressions and original clinical impressions were assessed by three NM physicians according to 6 quality dimensions (3-point scale) and an overall utility score (5-point scale). Each physician reviewed 12 of their own reports and 12 reports from other physicians. Bootstrap resampling was used for statistical analysis., Results: Of all evaluation metrics, domain-adapted BARTScore and PEGASUSScore showed the highest Spearman's ρ correlations ( ρ =0.568 and 0.563) with physician preferences. Based on these metrics, the fine-tuned PEGASUS model was selected as the top LLM. When physicians reviewed PEGASUS-generated impressions in their own style, 89% were considered clinically acceptable, with a mean utility score of 4.08 out of 5. Physicians rated these personalized impressions as comparable in overall utility to the impressions dictated by other physicians (4.03, P =0.41)., Conclusion: Personalized impressions generated by PEGASUS were clinically useful, highlighting its potential to expedite PET reporting.

Background: Parent psychological distress during childhood cancer treatment has short- and long-term implications for parent, child, and family well-being. Identifying targetable predictors of parental distress is essential to inform interventions. We investigated the association between household material hardship (HMH), a modifiable poverty-exposure defined as housing, food, or utility insecurity, and severe psychological distress among parents of children aged 1-17 years with acute lymphoblastic leukemia (ALL) enrolled on the multicenter Dana-Farber ALL Consortium Trial 16-001., Methods: This was a secondary analysis of parent-reported data. Parents completed an HMH survey within 32 days of clinical trial enrollment (T0) and again at 6 months into therapy (T1). The primary exposure was HMH at T0 and primary outcome was severe parental distress at T0 and T1, defined as a score greater than or equal to 13 on the Kessler-6 Psychological Distress Scale. Multivariable models were adjusted for ALL risk group and single parent status., Results: Among 375 evaluable parents, one-third (32%; n = 120/375) reported HMH at T0. In multivariable analyses, T0 HMH was associated with over twice the odds of severe psychological distress at T0 and T1 HMH was associated with over 5 times the odds of severe distress at T1., Conclusions: Despite uniform clinical trial treatment of their children at well-resourced pediatric centers, HMH-exposed parents-compared with unexposed parents-experienced statistically significantly increased odds of severe psychological distress at the time of their child's leukemia diagnosis, which worsened 6 months into therapy. These data identify a high-risk parental population who may benefit from early psychosocial and HMH-targeted interventions to mitigate disparities in well-being., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward., Competing Interests: Keri Toner, John Leonard, and Nita L. Seibel have no conflicts of interest to disclose. Shweta Jain is an employee of Seagen Inc. Heather Wasserstrom is an employee at Bristol Myers Squibb. John Leonard provides consulting advice for Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Janssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, and Sutro. Carl E. Allen is on advisory boards for SOBI and OPNA and has research support from Genentech. Kara Kelly is on scientific steering committee of Merck and Seagen., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL., (© 2023 Wiley Periodicals LLC.)

Purpose: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma., Methods and Materials: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement)., Results: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy., Conclusions: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose/objective: We compared the prognostic value of chest radiograph (CXR)- and computed tomography (CT)-derived definition of large mediastinal adenopathy (LMA) in pediatric Hodgkin lymphoma (HL)., Materials/methods: Total 143 patients treated for stage IIIB/IVB HL on COG AHOD0831 were included in this study. Six definitions of LMA were investigated: (i) mediastinal mass ratio on CXR (MR CXR ) > 1/3; (ii) mediastinal mass ratio on CT (MR CT ) > 1/3; (iii) mediastinal mass volume on CT (MV CT ) > 200 mL; (iv) normalized mediastinal mass volume (MV CT /thoracic diameter [TD]) > 1 mL/mm; (v) mediastinal mass diameter on CT (MD CT ) > 10 cm; and (vi) normalized mediastinal mass diameter (MD CT /TD) > 1/3., Results: Median age at diagnosis was 15.8 years (range: 5.2-21.3 years). In patients with a slow early response (SER) to chemotherapy, MV CT  > 200 mL, MD CT  > 10 cm, and MD CT /TD > 1/3 were associated with worse relapse-free survival (RFS) on MVA, while MR CXR  > 1/3, MR CT  > 1/3, and MV CT /TD > 1 mL/mm trended toward worse RFS; MD CT /TD was the most strongly prognostic for inferior RFS, with a hazard ratio of 6.41 for MD CT /TD > 1/3 versus ≤1/3 on MVA (p = .02)., Conclusion: LMA according to MV CT  > 200 mL, MD CT  > 10 cm, and MD CT /TD > 1/3 is associated with poor prognosis in advanced-stage HL patients with SER. The normalized mediastinal diameter, MD CT /TD > 1/3 appears to be the strongest predictor of inferior RFS., (© 2023 Wiley Periodicals LLC.)

The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response-adapted approach in high-risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET-based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUV max ) and peak SUV (SUV peak ) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV 2.5 /TLG 2.5 ) and 40% of the tumour SUV max (MTV 40% /TLG 40% ). TLG 2.5 was associated with event-free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut-off for TLG 2.5 was 1841. Four-year EFS was 92% for RER/TLG 2.5  up to 1841, 60% for RER/TLG 2.5  greater than 1841, 74% for SER/TLG 2.5  up to 1841 and 79% for SER/TLG 2.5  greater than 1841. Second EFS for RER/TLG 2.5  up to 1841 was 100%. Thus, RERs with a low baseline TLG 2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG 2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: The intrusive thoughts of cancer diagnosis, treatments, re-experiencing, and avoidance associated with post-traumatic stress symptoms (PTSS) can negatively affect Hodgkin lymphoma (HL) survivors. This study investigates the associations between experiences and beliefs and PTSS among adolescent survivors of intermediate-risk HL treated on the Children's Oncology Group (COG) AHOD0031 study. Methods: COG AHOD0031 participants completed self-report surveys at end of therapy concerning post-treatment medical conditions, activity limitations, fatigue, future concerns, exercise, and PTSS. Results: One thousand one hundred ten of 1721 participants in AHOD0031 completed the first survey at a median of 6.7 months post-diagnosis (interquartile range: 5.3-11.5 months), and of these, 736 (66.3%) completed a second survey at a median of 12.4 (10.1-17.6) months following the first. The mean PTSS score (ranging from 0 to 20) was 5.5 (standard deviation [SD] = 5.1) on survey 1 and 4.4 (SD = 4.8) on survey 2. Increased fatigue (odds ratio [OR] = 1.14, p  < 0.01), concerns for the future (OR = 1.13, p  < 0.01), activity limitations (OR = 1.05, p  < 0.01), and relapse history (OR = 2.18, p  < 0.05) were associated with higher PTSS scores in the initial survey. Increased fatigue (OR = 1.16, p  < 0.01), concerns for the future (OR = 1.14, p  < 0.01), activity limitations (OR = 1.05, p  < 0.05), and higher PTSS scores on the first survey (OR = 1.19, p  < 0.01) were associated with higher PTSS scores in the subsequent survey. Longer time since diagnosis (OR = 0.85, p  < 0.05; OR = 0.84, p  < 0.05) was associated with lower PTSS scores on both surveys. Conclusions: Based on our findings, future research should examine the onset and trajectory of PTSS among HL survivors, focusing on early recognition and intervention to improve quality of life.

Background: Although tumor genomic profiling has aided the advancement of targeted genetic therapy, its clinical integration remains a challenge in pediatric cancers due to lower mutation frequency and less available targeted drugs. There have been multiple novel studies examining molecular sequencing in pediatrics; however, many of these studies primarily utilized large-scale, genome-wide screening applications that limit applicable use due to the availability of testing. This study examined the institutional use of a targeted, clinically available approach to tumor genomic sequencing., Methods: A retrospective chart review was performed on pediatric patients with solid tumors who were managed at Roswell Park Comprehensive Cancer Center and underwent molecular testing of their tumor biopsy via OmniSeq from August 2016 to July 2021. Results were reviewed for mutations considered to be "actionable" by targeted therapy. Patients with actionable mutations were further examined to evaluate treatment course, receival of targeted therapy, and clinical outcomes., Results: We identified 64 pediatric patients consisting of 20 (31%) with CNS tumors and 44 (69%) with non-CNS tumors, ranging in age from 9 months to 21 years. Thirty-five total actionable mutations were identified amongst 27 patients (42%). Of these 27, 12 patients (44%) received at least 1 targeted drug against a respective actionable mutation, of which 6 patients (50%) achieved clinical benefit to therapy, including 1 complete response., Conclusions: The use of a clinically focused and readily available targeted molecular sequencing panel identified actionable mutations at a comparable rate to the large-scale, less readily available sequencing panels utilized in other studies. Half of our patients who received targeted therapy achieved a complete response or clinical benefit from therapy. Although targeted therapy has a role in pediatric cancer treatment, many newer drugs require further research on their safety and efficacy., (© 2023 Wiley Periodicals LLC.)

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions., Methods: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, resulting in institution-specific symptom management care pathway drafts. Institutional adaption teams distributed the 14 care pathway drafts to their respective teams; their feedback led to care pathway modifications., Results: Initial care pathway adaptation decision making was completed over a median of 4.2 (interquartile range 2.0-5.3) weeks per institution. Across all institutions and among 1350 statements, 551 (40.8%) were adopted, 657 (48.7%) were adapted, 86 (6.4%) were rejected and 56 (4.1%) were no longer applicable because of a previous decision. Most commonly, the reason for rejection was not agreeing with the statement (70/86, 81.4%). Institutional-level factors were not significantly associated with statement rejection., Conclusions: Acceptability of the 14 care pathways was evident by most statements being adopted or adapted. The adaptation process was accomplished over a relatively short timeframe. Future work should focus on evaluation of care pathway compliance and determination of the impact of care pathway-consistent care on patient outcomes., Trial Registration: clinicaltrials.gov, NCT04614662. Registered 04/11/2020, https://clinicaltrials.gov/ct2/show/NCT04614662?term=NCT04614662&draw=2&rank=1 ., (© 2023. The Author(s).)

Objective: We examined the social network support, composition, and structure of pediatric cancer caregivers., Methods: We used a self-report survey to collect egocentric social network data from 107 caregivers of pediatric cancer patients and calculated descriptive statistics to examine cancer-related support network composition, function, and structure. We then ran logistic regressions to examine the relationships between network characteristics and overall satisfaction with social support., Results: Family members were the most common source of emotional support and logistical support, and health care providers were the most common source of informational support. Participants perceived the "most helpful" forms of support as being: (1) emotional support from family and health care providers; (2) informational support from health care providers and other cancer caregivers; and (3) logistical support from family. Overall, caregivers wished that 9.8% of their network ties had provided more support, with family members being the most common alter type to disappoint caregivers and offer less support than needed/expected. Caregivers who reported higher network disappointment (having network members who offered less support than needed/expected) were significantly less satisfied with emotional support than those with lower network disappointment (Odds Ratio = 0.18, p = 0.02), and caregivers with higher network disappointment were significantly less satisfied with logistical support compared to those with lower network disappointment (Odds Ratio = 0.14, p = 0.01)., Conclusion: Our results show differences in the nature of social support provided by different types of network members. These findings have implications for tailoring social network interventions to improve caregiver and family outcomes., (© 2023 John Wiley & Sons Ltd.)

Purpose: Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline., Methods: In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274)., Results: Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests., Conclusions: Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Oral chemotherapy nonadherence is a challenge in clinical oncology. During therapy for acute lymphoblastic leukemia (ALL), poor adherence to 6-mercaptopurine (6MP) increases relapse risk. Clinically significant nonadherence is reported in 30% of children treated for ALL on Children's Oncology Group (COG) trials. Whether nonadherence rates vary across regimens with different treatment schedules and modes of administration is unknown. Methods: We conducted an exploratory, cross-sectional survey study on parents of children (1-18 years) receiving continuation therapy on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001. Treatment required weekly visits to the clinic and 14 days of oral 6MP every 3 weeks. Survey assessed self-reported sociodemographics, medication-taking, chemotherapy comprehension, and 6MP adherence; adherence survey items were developed from published surveys. Patients were grouped as nonadherent if they endorsed missing one 6MP dose during the last cycle, or more than one dose during prior cycles, for nonmedical reasons. Results: Sixty-two families completed the surveys, all of whom had evaluable adherence data. In total, 25% of patients met the study definition of nonadherence. Twenty-three percent reported that it was "not easy" to follow administration guidelines around the dairy intake and 57% requested more teaching and educational resources. Conclusion: Self-reported nonadherence to oral 6MP in the DFCI ALL Consortium is high, with rates similar to those observed in the COG. This suggests that the additional contact during weekly infusions on the DFCI is insufficient to address barriers affecting oral chemotherapy adherence.

Background: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear., Methods: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed., Results: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group., Conclusions: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.)., (Copyright © 2022 Massachusetts Medical Society.)

Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is virtually absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcome disparities, and identify health-equity intervention opportunities. We report the feasibility of a pediatric oncology multicenter therapeutic trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (88.9-93.1%) over 24 months. Trial-embedded SDoH data collection is feasible and acceptable and must be consistently included within future oncology trials., (© 2022 Wiley Periodicals LLC.)

Purpose: Smartphone-enabled micro-temporal data collection has potential to increase reliability, validity, and feasibility of participant-reported data and is a promising strategy for pediatric oncology supportive care and quality-of-life research. Given the demands of pediatric cancer caregiving, we sought to understand the feasibility and acceptability of smartphone data collection that included short surveys administered daily for 14 days via text message link., Methods: We recruited pediatric cancer caregivers, whose children (ages 0-18 years) were on active treatment, to complete a 14-day daily survey study via smartphone. We implemented our study procedures and examined feasibility through study enrollment rates, reasons for refusal, retention rates, number of reminders and number of completed surveys. We examined acceptability using caregiver ratings of survey length, burden, and ease of completion on a smartphone., Results: We recruited (N = 75) caregivers to the study and had an 84% enrollment rate. Reasons for declining participation included passive refusal (n = 13) and too busy (n = 1). The participant retention rate was 100% and compliance with daily survey completion was 99%. Most surveys were completed following two prompts and took participants 5 minutes or less to complete. Caregivers rated the surveys as easy to complete, low burden, and just right in length., Conclusion: A daily self-report, using a brief (≤5 minutes) survey administered on a smartphone via text message prompt, is a feasible and acceptable method. Future research should extend these findings to understand the generalizability across pediatric cancer caregiving contexts., (© 2022 Wiley Periodicals LLC.)

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003., (© 2022 by The American Society of Hematology.)

In pediatric cancer care, medication non-adherence is a significant driver of avoidable suffering and death. There is a lack of interventions designed for families of young children, where patient medication refusal/avoidance is a common barrier to adherence. We developed the CareMeds intervention which focuses on caregiver skills training to help young children take medicine calmly and without use of restraint techniques. The goal of this preliminary study was to assess the acceptability and feasibility of the CareMeds intervention. Caregivers of pediatric cancer patients (ages 2-10) whose children were on a home-based oral medication regimen were recruited to participate. Feasibility was examined through study enrollment and retention rates as well as reasons for refusal and drop out. Acceptability was evaluated through usability of and engagement with intervention components and an acceptability questionnaire. Feasibility: We recruited N = 9 caregivers to participate in this intervention pilot study and had a 75% enrollment rate. Reasons for declining included scheduling concerns ( n  = 2) and lack of interest ( n  = 1). The participant retention rate was 100% with 100% adherence to intervention sessions. Acceptability: Parents rated the sessions and resource materials as acceptable and reported frequent use of skills taught in the intervention. The CareMeds intervention is an acceptable and feasible strategy for caregivers of pediatric cancer patients and warrants future research to examine the efficacy of behavioral parenting skills interventions to improve medication adherence in young children.

Background/objectives: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial., Methods: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival., Results: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008)., Conclusion: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase., (© 2022 Wiley Periodicals LLC.)

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients., (© 2022 Wiley Periodicals LLC.)

Purpose: The Children's Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure., Methods and Materials: From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both)., Results: Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1-11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT., Conclusions: For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The molecular hallmark of childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA sequencing (RNA-seq) is a powerful next-generation sequencing technology that can simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multicenter phase 3 clinical trial for children with newly diagnosed ALL. The Dana-Farber Cancer Institute ALL Consortium Protocol 16-001 enrolled 173 patients with ALL who consented to optional studies and had samples available for RNA-seq. RNA-seq identified at least 1 alteration in 157 patients (91%). Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the following B-cell ALL (B-ALL) subgroups: high hyperdiploid (n = 36), ETV6-RUNX1/-like (n = 31), TCF3-PBX1 (n = 7), KMT2A-rearranged (KMT2A-R; n = 5), intrachromosomal amplification of chromosome 21 (iAMP21) (n = 1), hypodiploid (n = 1), Philadelphia chromosome (Ph)-positive/Ph-like (n = 16), DUX4-R (n = 11), PAX5 alterations (PAX5 alt; n = 11), PAX5 P80R (n = 1), ZNF384-R (n = 4), NUTM1-R (n = 1), MEF2D-R (n = 1), and others (n = 10). RNA-seq identified 141 nonsynonymous mutations in 93 patients (54%); the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Philadelphia chromosome-like gene signature prediction, results were concordant in 74 patients (94%). In conclusion, RNA-seq identified several clinically relevant genetic alterations not detected by conventional methods, which supports the integration of this technology into front-line pediatric ALL trials. This trial was registered at www.clinicaltrials.gov as #NCT03020030., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)